1. Field of the Invention
The present invention relates to novel carbapenem derivatives which have excellent antibiotic activity against a wide spectrum of bacteria, and more particularly to novel carbapenem derivatives which have a substituted imidazo[5,1-b]thiazole group at the 2-position on the carbapenem ring.
2. Background Art
Carbapenem derivatives, by virtue of potent antibiotic activity against a wide spectrum of bacteria, have been energetically studied as a highly useful xcex2-lactam agent, and Imipenem, Panipenem, and Meropenem have already been clinically used.
At the present time, both Imipenem and Panipenem, however, are used as a mixture due to instability against renal dehydropeptidase-1 (hereinafter abbreviated to xe2x80x9cDHP-1xe2x80x9d) in the case of Imipenem and in order to reduce nephrotoxicity in the case of Panipenem. Meropenem which has recently been marketed has a methyl group at the 1xcex2-position, so that it has increased stability against DHP-1 and thus can be used alone. The stability against DHP-1, however, is still unsatisfactory. The antibiotic activity also is not necessarily satisfactory against methicillin resistant Staphylococcus aureus (hereinafter abbreviated to xe2x80x9cMRSAxe2x80x9d), penicillin resistant Streptococcus pneumoneae (hereinafter abbreviated to xe2x80x9cPRSPxe2x80x9d), resistant Pseudomonas aeruginosa, enterococci, and Influenzavirus which currently pose serious clinical problems. Therefore, drugs useful for these bacteria responsible for infectious diseases have been desired in the art.
WO 96/28455 describes carbapenem derivatives having a novel aromatic heterocyclic imidazo[5,1-b]thiazolium-6-ylmethyl group at the 2-position of the carbapenem ring, WO 98/23623 describes carbapenem derivatives having an imidazo[5,1-b]thiazole group through a pyrrolidinylthio group at the 2-position of the carbapenem ring, and WO 98/32760 describes derivatives with a carbon atom on an imidazo[5,1-b]thiazole group being attached to the 2-position of the carbapenem ring.
An object of the present invention is to provide carbapenem derivatives which have potent antibiotic activity against MRSA, PRSP, Influenzavirus, and xcex2-lactamase-producing bacteria and are stable against DHP-1.
According to one aspect of the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt thereof: 
wherein
R1 represents a hydrogen atom or methyl;
R2 and R3, which may be the same or different, represent
a hydrogen atom,
a halogen atom,
lower alkyl on which one or more hydrogen atoms may be substituted by hydroxyl or amino,
lower alkylcarbonyl,
carbamoyl,
aryl, or
lower alkylthio; and
R4 represents
substituted lower alkylthio wherein one or more substituents of the alkyl portion, which may be the same or different, are selected from the group consisting of a halogen atom, nitro, azido, cyano, lower cycloalkyl, isothioureido, hydroxyl, lower alkoxy, phosphonoxy, formyl, lower alkylcarbonyl, arylcarbonyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, amino, N-lower alkylamino, N,N-di-lower alkylamino, formylamino, lower alkylcarbonylamino, aminosulfonylamino, (N-lower alkylamino)sulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, formimidoylamino, acetimidoylamino, guanidino, amindsulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, aryl, a monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms, which may be the same or different, pyridinium-1-yl, 1-azonia-4-azabicyclo[2,2,2]oct-1-yl, and 4-lower alkyl-1,4-diazoniabicyclo[2,2,2]oct-1-yl wherein the lower alkyl portion may be substituted by one or more groups selected from the group consisting of a halogen atom, hydroxyl, carbamoyl, and amino,
lower cycloalkylthio wherein one or more hydrogen atoms of the cycloalkyl portion may be substituted by a group selected from the group consisting of a halogen atom, nitro, cyano, hydroxyl, carbamoyl, and amino,
C2-4 alkenylthio,
C2-4 alkynylthio,
substituted arylthio wherein one or more substituents of the aryl portion, which may be the same or different, are selected from the group consisting of a halogen atom, nitro, cyano, hydroxyl, carbamoyl, and amino,
thio substituted by a monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms which may be the same or different, wherein, when the ring contains a nitrogen atom, lower alkyl optionally having carbamoyl may be attached to the nitrogen atom and the nitrogen atom may be in the form of a quaternary ammonium atom,
substituted lower alkylsulfinyl wherein one or more substituents of the alkyl portion, which may be the same or different, are selected from the group consisting of a halogen atom, hydroxyl, carbamoyl, and amino,
substituted lower alkylsulfonyl wherein one or more substituents of the alkyl portion, which may be the same or different, are selected from the group consisting of a halogen atom, hydroxyl, carbamoyl, and amino, or
sulfonyl substituted by a monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms which may be the same or different, wherein, when the ring contains a nitrogen atom, lower alkyl optionally having carbamoyl may be attached to the nitrogen atom and the nitrogen atom may be in the form of a quaternary ammonium atom.
The carbapenem derivatives represented by formula (I) have potent antibiotic activities against a wide spectrum of Gram-positive bacteria and Gram-negative bacteria. The compounds represented by formula (I) have potent antibiotic activity particularly against MRSA, PRSP, Influenzavirus, and xcex2-lactamase-producing bacteria. The carbapenem derivatives of the present invention advantageously have low toxicity and high safety.
As used herein, the term xe2x80x9clower alkylxe2x80x9d or xe2x80x9clower alkoxyxe2x80x9d as a group or a part of a group means straight-chain or branched C1-6, preferably C1-4, alkyl or alkyloxy. Examples of the lower alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl. Examples of the lower alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, and t-butoxy.
The term xe2x80x9clower cycloalkylxe2x80x9d means C3-6 monocyclic alkyl.
The term xe2x80x9chalogen atomxe2x80x9d means a fluorine, chlorine, bromine, or iodine atom.
The term xe2x80x9carylxe2x80x9d as a group or a part of a group means a six- to 10-membered monocyclic or bicyclic aromatic carbocyclic ring, and examples thereof include phenyl and naphthyl with phenyl being preferred.
The term xe2x80x9chetero atomxe2x80x9d as used herein means a nitrogen atom, an oxygen atom, or a sulfur atom.
The xe2x80x9cmonocyclic or bicyclic heterocyclic ring containing one or more hetero atomsxe2x80x9d preferably means a five- to 12-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring containing 1 to 4 hetero atoms. The hetero atom constituting the heterocyclic ring is preferably one or two nitrogen atoms.
Examples of the heterocyclic ring include pyrrolidine, piperidine, and pyridine.
R1 preferably represents methyl.
R2 and R3, which may be the same or different, preferably represent a hydrogen atom or lower alkylthio, more preferably a hydrogen atom or methylthio, particularly preferably a hydrogen atom.
R4 preferably represents
substituted lower alkylthio wherein one or more substituents of the alkyl portion, which may be the same or different, are selected from the group consisting of a halogen atom, azido, isothioureido, hydroxyl, phosphonoxy, lower alkylcarbonyl, carbamoyl, amino, formylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, formimidoylamino, acetimidoylamino amino, guanidino, aryl, a pyridine ring, pyridinium-1-yl, 1-azonia-4-azabicyclo[2,2,2]oct-1-yl, and 4-lower alkyl-1,4-diazoniabicyclo[2,2,2]oct-1-yl in which lower alkyl may be substituted by one or more groups selected from the group consisting of a halogen atom, hydroxyl, carbamoyl, and amino,
thio substituted by a heterocyclic ring selected from the group consisting of pyrrolidine, piperidine, and pyridine, wherein lower alkyl optionally having carbamoyl may be attached to the nitrogen atom in the ring and the nitrogen atom may be in the form of a quaternary ammonium atom,
lower alkylsulfinyl optionally substituted by hydroxyl,
lower alkylsulfonyl optionally substituted by hydroxyl, or
sulfonyl substituted by a heterocyclic ring selected from the group consisting of pyrrolidine, piperidine, and pyridine, wherein lower alkyl optionally having carbamoyl may be attached to the nitrogen atom in the ring and the nitrogen atom may be in the form of a quaternary ammonium atom.
R4 more preferably represents trifluoromethylthio, 2-fluoroethylthio, 2-bromoethylthio, 2-azidoethylthio, 2-(isothioureidoethyl)thio, 2-hydroxyethylthio, (2R)-2,3-dihydroxypropylthio, 2-phosphonoxyethylthio, 2-oxo-propylthio, carbamoylmethylthio, 2-aminoethylthio, 3-aminopropylthio, 6-aminohexylthio, (2R)-3-amino-2-hydroxypropylthio, 2-formylaminoethylthio, 2-(aminosulfonylamino)ethylthio, 2-[(N,N-dimethylamino)sulfonyl-amino]ethylthio, 2-(formimidoylamino)ethylthio, 2-(acetimidoylamino)ethylthio, 3-(acetimidoylamino)propylthio, 2-guanidinoethylthio, 3-guanidinopropylthio, benzylthio, (pyridin-2-yl)methylthio, 2-(pyridinium-1-yl)ethylthio, 2-(1-azonia-4-azabicyclo[2,2,2]oct-1-yl)ethylthio, (3S)-3-pyrrolidinylthio, 4-piperidinylthio, (pyridin-2-yl)thio, (pyridin-4-yl)thio, (1-carbamoylmethylpyridinium-2-yl)thio, 2-hydroxyethylsulfinyl, 2-hydroxyethylsulfonyl, or (pyridin-4-yl)sulfonyl. Among them, substituted lower alkylthio is more preferred, and guanidino-substituted lower alkylthio or pyrrolidinylthio is particularly preferred.
Among the compounds represented by formula (I), a group of preferred compounds include those wherein
R4 represents
substituted lower alkylthio,
thio substituted by a monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms which may be the same or different,
substituted lower alkylsulfinyl,
substituted lower alkylsulfonyl, or
sulfonyl substituted by a monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms which may be the same or different, wherein, when the ring contains a nitrogen atom, lower alkyl optionally having carbamoyl may be attached to the nitrogen atom and the nitrogen atom may be in the form of a quaternary ammonium atom.
Another group of preferred compounds include those wherein
R4 represents
substituted lower alkylthio,
optionally substituted lower cycloalkylthio,
C2-4 alkenylthio,
C2-4 alkynylthio,
substituted arylthio,
thio substituted by a monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms which may be the same or different,
substituted lower alkylsulfinyl, or
substituted lower alkylsulfonyl.
A group of more preferred compounds include those wherein
R1 represents a hydrogen atom or methyl,
R2 and R3, which may be the same or different, represent a hydrogen atom or lower alkylthio, and
R4 represents
substituted lower alkylthio wherein one or more substituents thereof are selected from the group consisting of a halogen atom, azido, isothioureido, hydroxyl, phosphonoxy, lower alkylcarbonyl, carbamoyl, amino, formylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonyl-amino, formimidoylamino, acetimidoylamino, guanidino, aryl, pyridyl, pyridinium-1-yl, 1-azonia-4-azabicyclo[2,2,2]oct-1-yl, and 4-lower alkyl-1,4-diazoniabicyclo[2,2,2]oct-1-yl in which lower alkyl may be substituted by one or more groups selected from the group consisting of a halogen atom, hydroxyl, carbamoyl, and amino,
thio substituted by a heterocyclic ring selected from the group consisting of pyrrolidine, piperidine, and pyridine, wherein lower alkyl optionally having carbamoyl may be attached to the nitrogen atom in the ring and the nitrogen atom may be in the form of a quaternary ammonium atom,
lower alkylsulfinyl optionally substituted, by hydroxyl,
lower alkylsulfonyl optionally substituted by hydroxyl, or
sulfonyl substituted by a heterocyclic ring selected from the group consisting of pyrrolidine, piperidine, and pyridine, wherein lower alkyl optionally having carbamoyl may be attached to the nitrogen atom in the ring and the nitrogen atom may be in the form of a quaternary ammonium atom.
Another group of more preferred compounds include those wherein
R1 represents a hydrogen atom or methyl,
R2 and R3, which may be the same or different, represent a hydrogen atom or lower alkylthio, and
R4 represents substituted lower alkylthio wherein one or more substituents thereof are selected from the group consisting of a halogen atom, azido, isothioureido, hydroxyl, phosphonoxy, lower alkylcarbonyl, carbamoyl, amino, formylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonyl-amino, formimidoylamino, acetimidoylamino, guanidino, aryl, pyridyl, pyridinium-1-yl, 1-azonia-4-azabicyclo[2,2,2]oct-1-yl, and 4-lower alkyl-1,4-diazoniabicyclo[2,2,2]oct-1-yl in which one or more hydrogen atoms on lower alkyl may be substituted by a halogen atom, hydroxyl, carbamoyl, or amino.
A group of further preferred compounds include those wherein R1 represents methyl and R2 and R3 represent a hydrogen atom.
A group of particularly preferred compounds include those wherein R1 represents methyl, R2 and R3 represent a hydrogen atom and R4 represents amino or guanidino-substituted lower alkylthio or pyrrolidinylthio, more preferably those wherein R1 represents methyl, R2 and R3 represent a hydrogen atom and R4 represents 2-aminoethylthio, 2-guanidinoethylthio, or (3S)-pyrrolidin-3-ylthio.
Salts of the compounds represented by formula (I) are pharmaceutically acceptable salts, and include, for example, inorganic salts, such as lithium, sodium, potassium, calcium, and magnesium salts, ammonium salts, salts with organic bases, such as triethylamine and diisopropylethylamine, salts with mineral acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid, or salts with organic acids, such as acetic acid, carbonic acid, citric acid, malic acid, oxalic acid, and methanesulfonic acid. Preferred are sodium salts, potassium salts, and hydrochlorides.
Specific examples of carbapenem derivatives represented by formula (I) according to the present invention include, but are not limited to:
1. sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-hydroxyethyl)thioimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate;
2. sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-hydroxyethyl)sulfinylimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers);
3. sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-hydroxyethyl)sulfonylimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate;
4. sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-hydroxyethyl)thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate;
5. sodium (1S,5R,6S)-2-[7-(2-aminoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;
6. sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(2-phosphonoxyethyl)thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate;
7. sodium (1S,5R,6S)-2-[7-(2-azidoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;
8. sodium (5R,6S)-2-[7-(2-aminoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;
9. sodium (1S,5R,6S)-2-(7-carbamoylmethylthio-5-methylthioimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;
10. (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[2-(pyridinium-1-yl)ethyl]thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (intramolecular salt);
11. (5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-[2-(pyridinium-1-yl)ethyl]thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (intramolecular salt);
12. sodium (1S,5R,6S)-2-[7-(2-formimidoylaminoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;
13. sodium (1S,5R,6S)-2-[7-(2-acetimidoylaminoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;
14. sodium (1S,5R,6S)-2-[7-(2-fluoroethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;
15. sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[5-methylthio-7-(2-phosphonoxyethyl)thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate;
16. sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-hydroxyethyl)thio-5-methylthioimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate;
17. sodium (1S,5R,6S)-2-[7-(2-aminoethyl)thio-5-methylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;
18. sodium (1S,5R,6S)-2-[7-(2-formylaminoethyl)-thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;
19. sodium (1S,5R,6S)-2-[7-(3-aminopropyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;
20. sodium (1S,5R,6S)-2-[7-(2-guanidinoethyl)-thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;
21. sodium (1S,5R,6S)-2-[7-(3-acetimidoylaminopropyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;
22. (1S,5R,6S)-2-[7-(6-aminohexyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylic acid;
23. sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-((3S)-pyrrolidin-3-yl)thioimidazo[5,1-b]-thiazol-2-yl]-1-carbapen-2-em-3-carboxylate;
24. sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-trifluoromethylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate;
25. (1S,5R,6S)-2-(7-carbamoylmethylthioimidazo-[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylic acid;
26. (1S,5R,6S)-2-[7-(2-aminosulfonylaminoethyl)-thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylic acid;
27. sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(piperidin-4-yl)thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate;
28. sodium (1S,5R,6S)-2-[7-(2-N,N-dimethylaminosulfonylaminoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;
29. (1S,5R,6S)-2-[7-[2-(1-azonia-4-azabicyclo-[2,2,2]oct-1-yl)ethyl]thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (intramolecular salt) hydrochloride;
30. (1S,5R,6S)-2-[7-(3-guanidinopropyl)thioimidazo-[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylic acid;
31. sodium (1S,5R,6S)-2-[7-(2-bromoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;
32. sodium (1S,5R,6S)-2-(7-benzylthioimidazo-[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;
33. (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-isothioureidoethyl)thioimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylic acid;
34. sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-2-yl)methylthioimidazo[5,1-b]-thiazol-2-yl]-1-carbapen-2-em-3-carboxylate;
35. sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-2-yl)thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate;
36. (1S,5R,6S)-2-[7-(1-carbamoylmethylpyridinium-2-yl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (intramolecular salt);
37. sodium (1S,5R,6S)-2-[7-((2R)-2,3-dihydroxypropyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;
38. sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(2-oxopropyl)thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate;
39. sodium (1S,5R,6S)-2-[7-((2R)-3-amino-2-hydroxypropyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;
40. sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-4-yl)thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate; and
41. sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-4-yl)sulfonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate.
The compounds represented by formula (I) according to the present invention are preferably produced according to the following scheme: 
wherein R1, R2, R3, and R4 each have the same meaning as defined in formula (I), R5 represents a hydrogen atom or a protective group of hydroxyl, for example, t-butyldimethylsilyl, trimethylsilyl, triethylsilyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, or allyloxycarbonyl; R6 represents a protective group of carboxyl, for example, 4-nitrobenzyl, 4-methoxybenzyl, diphenylmethyl, t-butyldimethylsilyl, or allyl; R7 represents lower alkyl, preferably n-butyl or methyl; R8 and R9 have the same meaning as R2 and R3 or represent a group in which a functional group, for example, hydroxyl, amino, or carboxyl, contained in R2 and R3 has been protected by a conventional protective group; and R10 has the same meaning as R4 or represents a group in which a functional group, for example, hydroxyl, amino, or carboxyl, contained, in R4 has been protected by a conventional protective group. The term xe2x80x9cconventional protective groupxe2x80x9d as used herein refers to a protective group described in Protective Groups in organic Synthesis, Theodora W. Greene and Peter G. M. Wuts, published by John Wiley and Sons, Inc.
The compound of formula (II) indicated in the scheme in the first step can be synthesized by the conventional process, and the tin compound of formula (IV) indicated in the scheme in the second step can be synthesized by a process described in WO 98/32760.
In the first step, the compound of formula (II) can be converted to the compound of formula (III) by the following method. Specifically, the compound of formula (II) is reacted with one equivalent or an excessive amount of trifluoromethanesulfonic anhydride in the presence of an organic base, preferably diisopropylethylamine, in an amount of one equivalent or an excessive amount relative to trifluoromethanesulfonic anhydride in an inert solvent, such as acetonitrile, tetrahydrofuran, dichloromethane, or toluene or a mixed solvent composed of the above inert solvents, at a temperature of xe2x88x9250xc2x0 C. to +50xc2x0 C. for 10 min to 24 hr, followed by conventional separation and purification to give the compound of formula (III).
Next, in the second step, the compound of formula (III) can be converted to the compound of formula (V) by the following method. Specifically, the compound of formula (III) is reacted with one equivalent or an excessive amount of the compound of formula (IV) in the presence of 0.001 to 1 equivalent of a palladium catalyst, for example, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), or tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, 0.01 to 1 equivalent of a phosphine ligand, for example, triphenylphosphine, tri-2-furylphosphine, tri-2-thienylphosphine, or tris(2,4,6-trimethoxyphenyl)-phosphine, and 1 to 10 equivalents of an additive, for example, zinc chloride, lithium chloride, or cesium fluoride alone or in combination thereof, in an inert solvent, for example, tetrahydrofuran, dimethoxyethane, dioxane, acetonitrile, acetone, ethanol, dimethylsulfoxide, sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, or hexamethylphosphoric triamide or a mixed solvent composed of the above inert solvents, at 0xc2x0 C.-100xc2x0 C. for 10 min to 7 days, followed by conventional post-treatment to give the compound of formula (V).
Finally, in the third step, the protective group in the compound of formula (V) may be removed by a deprotection reaction in one stage or plural stages depending on the kinds of the protective groups to give the compound of formula (I).
In this case, the deprotection reaction for removing the protective group may be carried out by conventional methods commonly known in the art, although it varies depending upon the kinds of protective groups used. When any one of or all the protective groups can be removed under acidic conditions, a mineral acid such as hydrochloric acid, an organic acid such as formic acid, acetic acid or citric acid, or a Lewis acid such as aluminum chloride may be used. On the other hand, when the protective groups are removed under reducing conditions, a catalytic reduction in the presence of a variety of catalysts, or a metallic reducing agent such as zinc or iron may be used. When R5 is a silyl-type protective group such as t-butyldimethylsilyl, trimethylsilyl, or triethylsilyl, it can be easily removed with a fluorine ion reagent such as tetrabutylammonium fluoride. When R5 is allyloxycarbonyl and R6 is allyl, the protective groups can be easily removed with a variety of palladium complexes, for example, tetrakis(triphenylphosphine)palladium(0).
The compounds of formula (I) thus obtained can be isolated and purified, for example, by crystallization, chromatography with nonionic macro-high porous resin, gel filtration with Sephadex or the like, or reverse phase column chromatography on silica gel.
The compounds according to the present invention have potent antibiotic activity against a wide spectrum of Gram-positive and Gram-negative bacteria, and, in addition, exhibit potent antibiotic activity against MRSA, PRSP, Influenzavirus, and xcex2-lactamase-producing bacteria. Further, they have no significant toxicity and are stable against DHP-1. Thus, the compounds according to the present invention can be used for the treatment of infectious diseases caused by various pathogenic bacteria in animals including humans. A pharmaceutical composition comprising as active ingredient the compound according to the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally by administration routes, for example, intravenous injection, intramuscular injection, or subcutaneous, rectal, or percutaneous administration, to a human and a non-human animal.
The pharmaceutical composition comprising as active ingredient the compound according to the present invention can be formulated into appropriate dosage forms, primarily into any one of the preparation forms including: injections such as intravenous injection or intramuscular injection; preparations for oral administration such as capsules, tablets, granules, powders, pills, particulates, or troches; preparations for rectal administration; and fatty suppositories, depending on its administration routes.
These preparations can be prepared by the usual methods with pharmaceutically acceptable additives for preparations commonly used in the art, for example, excipients, fillers, binders, humidifiers, disintegrants, surface active agents, lubricants, dispersants, buffers, preservatives, dissolution aids, antiseptics, flavoring agents, analgesic agents, and stabilizers.
Such non-toxic additives usable herein include, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose or a salt thereof, gum arabic, polyethylene glycol, syrup, petrolatum, glycerin, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, and sodium phosphate.
The dosage may be appropriately determined, for example, in consideration of the dosage route and the age, sex and condition of patients, and the preparation may be administered for the treatment of infectious diseases usually in an amount of about 25 mg to 2000 mg, preferably 50 mg to 1000 mg, per day per adult in one or several portions.